25 November 2010 EMA/HMPC/3206/2009 Committee on Herbal Medicinal Products (HMPC) Assessment report on Quercus robur L., Quercus petraea (Matt.) Liebl., Quercus pubescens Willd., cortex Based on Article 16d (1), Article 16f and Article 16h of Directive 2001/83/EC as amended (traditional use) Final Herbal substance(s) (binomial scientific name of Quercus robur L. the plant, including plant part) Quercus petraea (Matt.) Liebl. Quercus pubescens Willd. Cortex Herbal preparation(s) i) Herbal substance Quercus robur L., Quercus petraea.(Matt.) Liebl., Quercus pubescens Willd., oak bark. Cut and dried bark from the fresh young branches. ii) Herbal preparations - Comminuted herbal substance - Powdered herbal substance Dry extract (5.0-6.5:1), extraction solvent: ethanol 50% V/V Pharmaceutical forms Herbal substance or herbal preparations in solid or liquid dosage forms for oral use or as herbal tea for oral use. Herbal substance or comminuted herbal substance for decoction preparation for oromucosal cutaneous or anorectal use. Rapporteur Dr Ewa Widy-Tyszkiewicz Assessor(s) Dr Ewa Widy-Tyszkiewicz 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7051 E-mail [email protected] Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2011. Reproduction is authorised provided the source is acknowledged. Table of contents Table of contents ...................................................................................................................2 1. Introduction.......................................................................................................................3 1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof .3 1.2. Information about products on the market in the Member States .............................. 5 1.3. Search and assessment methodology.................................................................... 6 2. Historical data on medicinal use ........................................................................................6 2.1. Information on period of medicinal use in the Community ........................................ 6 2.2. Information on traditional/current indications and specified substances/preparations ... 7 2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications..................................................................................... 10 3. Non-Clinical Data .............................................................................................................11 3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof ......................................................... 11 3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof ......................................................... 17 3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof ..................................................................... 18 3.4. Overall conclusions on non-clinical data............................................................... 20 4. Clinical Data.....................................................................................................................20 4.1. Clinical Pharmacology ....................................................................................... 20 4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents ...................................................................... 20 4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents ...................................................................... 20 4.2. Clinical Efficacy ................................................................................................ 21 4.2.1. Dose response studies.................................................................................... 21 4.2.2. Clinical studies (case studies and clinical trials).................................................. 21 4.2.3. Clinical studies in special populations (e.g. elderly and children)........................... 21 4.3. Overall conclusions on clinical pharmacology and efficacy ...................................... 21 5. Clinical Safety/Pharmacovigilance...................................................................................21 5.1. Overview of toxicological/safety data from clinical trials in humans.......................... 21 5.2. Patient exposure .............................................................................................. 21 5.3. Adverse events and serious adverse events and deaths ......................................... 21 5.4. Laboratory findings .......................................................................................... 22 5.5. Safety in special populations and situations ......................................................... 22 5.6. Overall conclusions on clinical safety................................................................... 23 6. Overall conclusions ..........................................................................................................23 Annex ..................................................................................................................................23 Assessment report on Quercus robur L., Quercus petraea (Matt.) Liebl., Quercus pubescens Willd., cortex EMA/HMPC/3206/2009 Page 2/23 1. Introduction 1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof Herbal substance(s) The herbal substance is mentioned in several well known handbooks such as Madaus (1938), Martindale (2007), Bisset and Wichtl (1994), PDR for Herbal Medicines (2000; 2004), German Comission E Monograph and European Pharmacopoeia 6.0, Duke’s Handbook of Medicinal Herbs (2002), Mills and Bone (2000), Schulz et al. 1998, Wagner and Wiesenauer 1995; Weiss and Fintelman (1999). In the European Pharmacopoeia, it is described as the cut and dried bark of young branches and the lateral shoots of Quercus robur, Quercus petraea and/or Quercus pubescens. It contains a minimal amount of 3% of tannins, expressed as pyrogallol, calculated with reference to the dried herbal substance. The plant belongs to the family Fagacae, subfamily Quercoideae, genus Quercus. Oak bark is harvested in spring from March to April. The oak bark contains highly variable amount of tannins (8-20%). The tannin content depends on the time of the harvest, age of the branches and on the method of assay used. Tannins are polyphenolic secondary metabolites of higher plants. They comprise either: galloyl esters and their derivatives (gallotannins, ellagitannins and complex tannins) or they are oligomeric and polymeric proanthocyanidins and can possess different interflavanyl coupling and substitution patterns (condensed tannins) (Okuda et al. 1993; 2005). The oak bark contains both hydrolyzable and condensed tannins (Ahn and Gstirner 1971; 1973; Bate-Smith 1972; Bruneton 1995; Chen 1970; Evans 2009; Glasl 1983; Grundhöfer et al. 2001; Haddock et al. 1982; Haslam 2007; Haslam and Cai 1994; Herve du Penhoat et al. 1991a, 1991b; Ikram and Nowshad 1977; Ishimaru et al. 1987; Khanbabaee and van Ree 2001; König et al. 1994; Mämmelä et al. 2000; Niemetz and Gross 2005; Pallenbach et al. 1991, 1993; Roux and Evelyn 1958; Salminen et al. 2004; Scalbert et al. 1988; 1989, 1990; Schofield et al. 2001; Vivas et al. 1995; Vovk et al. 2003; Yoshida 1984). Hydrolysable tannins They are previously known as pyrogallol tannins. Principal types of hydrolysable tannins are gallotannins and elagitannins. They are polyesters of glucose and can be hydrolysed by acids or enzymes sych as tannase. They release sugar upon hydrolysis and either gallic acid or hexahydroxydiphenic acid. Phenolic acids: gallic acid is present in gallotannins or hexahydroxydiphenic acid in ellagitannins. The latter undergoes lactonization to produce ellagic acid (Okuda et al. 1989). Gallotannins are the simplest hydrolysable tannins, containing a polyphenolic and a polyol residue (mostly derived from D-glucose). Tannic acid is a polymer of about eight monomers of gallic acid and glucose. Ellagitannins (formed from the gallotannins by the oxidative coupling of at least two galloyl units, yielding an axially chiral hexahydroxydiphenoyl (HHDP) unit) grandinin, castalagin, pedmolagin, pedunculagin, roburin A-E, vescalin, vescalagin, 2,3-(S)-hexahydroxy diphenoyl glucose (Bate-Smith 1972; Feldman 2005; Herve du Penhoat et al. 1991a; 1991b; Mämmelä et al. 2000; Peng et al. 1991; Vivas et al. 1995). Assessment report on Quercus robur L., Quercus petraea (Matt.) Liebl., Quercus pubescens Willd., cortex EMA/HMPC/3206/2009 Page 3/23 Flavano-ellagitannins: acutissimins A an B, eugenigrandin A, guajavin B, stenophyllanin C (Khanbabaee and van Ree 2001). Procyanidinoellagitannin: mongolicanin. Ellagitannins are instable and hydrolysed over time with formation of free ellagic acid and decrease of their solubility (Charrier et al. 1992; Klumpers et al. 1994; König and Scholz 1994; Mämmelä et al. 2000; Simon et al. 1999). Present data suggest, that the pyrogallol phenols (+)-gallocatechin and leucodelphinidin,